Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.11.1.8 (thyroid peroxidase)
3,116 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have studied the ability of lymphocytes from the blood, thyroid and lymph nodes of patients with autoimmune thyroid disease (AITD) to produce autoantibodies to thyroglobulin (Tg) and/or thyroid peroxidase (TPO) in SCID mice. Human IgG class Tg and/or TPO antibodies were detectable in plasma from SCID mice 7 days after transfer of 15-25 x 10(6) cells/mouse and the highest levels were recorded 2-3 weeks later. In contrast, Tg and/or TPO antibodies were undetectable in recipients of lymphocytes from thyroid antibody negative controls. AITD thyroid lymphocytes produced the most antibody in recipient mice and lower levels were observed in recipients of AITD blood and lymph node lymphocytes. The amounts of Tg and/or TPO antibody detected were in accordance with the ability of thyroid and lymph node lymphocytes to secrete these autoantibodies spontaneously in culture (indicating the presence of cells activated in the patient) and with the capacity of blood lymphocytes (probably B memory cells) to secrete Tg and/or TPO antibodies in culture in response to pokeweed mitogen. Tg antibodies in plasma from SCID recipients of thyroid lymphocytes were of subclasses IgG1, IgG2 and IgG4 and the proportions closely resembled those of the donor's serum Tg antibodies. Blood lymphocytes transferred to SCID recipients were also able to produce Tg antibodies of subclasses 1, 2 and 4 but the subclass distribution varied between mice and the reason for this is not clear at present. Since SCID mice provide an environment in which B lymphocytes from patients with AITD can be activated without mitogen to secrete thyroid antibodies, this model will provide a powerful system for elucidating the mechanisms regulating the secretion of human antibodies to Tg and TPO.
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PMID:Severe combined immunodeficient (SCID) mice: a model for investigating human thyroid autoantibody synthesis. 201 11

Thyroid tissues from patients with Hashimoto's thyroiditis (HT) have been xenografted to both severe combined immunodeficiency (SCID) mice and nude mice to study the intrathyroidal lymphocytes which were expected to migrate from the xenografts in the SCID mice. Peripheral blood mononuclear cells from HT, Graves' disease, and normal donors have also been separately engrafted. SCID mice, but not nude mice with HT thyroid grafts produce human immunoglobulins. More immunoglobulin G (IgG), but less IgM and IgA is produced in SCID mice with HT thyroid grafts (SCID-TH), compared to SCID mice injected with peripheral blood mononuclear cells from patients with HT or normal donors (SCID-PB), suggesting that different B cell subpopulations were active in the SCID-PB vs. SCID-TH. Production of IgG by SCID-PB and SCID-TH was maintained 6 weeks after engraftment, and decreased thereafter. SCID mice but not nude mice grafted with HT thyroid tissue produce antibodies to thyroglobulin and thyroperoxidase. Lymphocytes within intact HT thyroid grafts persist in SCID mice, and migrate to the spleen, whereas human lymphocytes do not survive in the thyroid grafts or other tissues of the nude mouse. In 6 weeks, the xenografts in nude mice became histologically normal. In contrast, xenografts from SCID mice showed more marked inflammatory changes than in the original human lesion, although the ratio of T/B cells is unchanged. This worsening of the lesion may relate to the increase in activation of the T-lymphocytes.
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PMID:Reconstitution of severe combined immunodeficient mice with intrathyroidal lymphocytes of thyroid xenografts from patients with Hashimoto's thyroiditis. 767 24

To study the role of Th0 and Th1 cells in autoimmune thyroid disease, thyroid tissues from patients with Graves' disease (GD), Hashimoto's thyroiditis (HT), and colloid nodular disease were xenografted into SCID mice, followed by ip injection of peripheral blood mononuclear cells (PBMC), T cell lines, and T cell clones (TCC). The antigen-specific TCC reactive to TSH receptor (TSH-R), thyroid peroxidase (TPO), or thyroglobulin (Tg), and their respective peptides, were classified into Th0 (secreting IL-4 and/or IL-5 and IFN-gamma) and Th1 (secreting IFN-gamma) according to their cytokine profile. Engraftment of autologous or HLA-matched allogeneic CD4+ thyroid-specific clones with Th0 or Th1 phenotypes induced the production of total IgG and thyroid-specific autoantibodies by B cells present in xenografted thyroid tissues. TSH-R-specific clones mainly enhanced thyroid-stimulating antibodies (TSAb) production, while clones reactive to TPO and Tg increased the synthesis of TPO and Tg autoantibodies. Total IgG production, but not TSAb, was also stimulated by PBMC and TSH-R lines. TSAb correlated with the viability and hyperplasia of thyroid follicles, but not with the serum T3 levels, which were normal. Thyroid tissue viability was maintained or increased by antigen-specific Th0 clones, and decreased by Th1 clones reactive to TSH-R or TPO. Thyroid lymphocytic infiltration was variable; however, Th0 and Th1 clones from HT patients caused high degree of lymphocytic infiltration compared to the control groups. These results demonstrate for the first time that T cells clones reactive to specific epitopes of TSH-R, TPO, or Tg can generate antibody-mediated and/or cell-mediated responses in the xenografted thyroid tissue microenvironment. Such effects depend on clonal specificity, HLA class II restriction, and cytokine profile of the clone. Th0 clones reactive to TSH-R stimulate both total IgG production and TSAb in SCID mice engrafted with thyroid tissue from GD patients. Th0 and Th1 clones specific for TPO and Tg also function as helper T cells, stimulating total IgG synthesis and autoantibodies against TPO and Tg. Th1 clones may also cause tissue destruction in GD and HT.
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PMID:Evaluating the role of Th0 and Th1 clones in autoimmune thyroid disease by use of Hu-SCID chimeras. 940 Jun 25

Mobilized peripheral blood progenitor cells (PBPC) are an attractive target for the retrovirus-mediated transfer of cytostatic drug resistance genes. We analyzed NOD/SCID mouse repopulating CD34+ PBPC from cancer patients following retroviral Transwell transduction in various cytokine combinations with the FMEV-based (Friend-mink cell focus forming/murine embryonic stem cell virus) hybrid vector SF-MDR carrying the human multidrug resistance-1 (MDR1) gene. Five to 10 weeks following transplantation of 2.0 x 10(6) CD34+ PBPC into NOD/SCID mice we observed medium to high levels of human cell engraftment with up to 33%. The extent of vector-marked human cells was assessed by a quantitative real-time polymerase chain reaction (PCR). SF-MDR gene transfer into long-term in vivo repopulating human hematopoietic cells was optimal in the presence of either IL-3/IL-6/SCF/FL or FL/TPO/SCF resulting in three-fold (12.4% +/- 1.7%) or four-fold (16.5% +/- 6.8%) higher average proportions of gene-marked human cells in NOD/SCID mice as compared to IL-3 alone (P < 0.01). In conclusion, we could optimize the engraftment capacity and the retroviral gene transfer to CD34+ PBPC using cocktails of early acting cytokines in combination with the recombinant fibronectin fragment CH-296. Our data suggest that the NOD/SCID model provides a valid assay to estimate the gene transfer efficiency to repopulating human PBPC that may be achievable in clinical autologous transplantation settings.
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PMID:Human multidrug resistance-1 gene transfer to long-term repopulating human mobilized peripheral blood progenitor cells. 1093 4

In view of the limited potential for rapid hematological recovery after transplantation of umbilical cord blood cells (UCB) in adults, we have attempted to expand CD34+ selected hemopoietic stem cells (HSC) and progenitors in 2-week cultures of whole graft pools in the presence or absence of serum and stromal layers, and with various cytokine combinations including (1) FL + TPO; (2) FL + TPO plus SCF and/or IL6; or (3) SCF + IL6. Both in the input material and cultured grafts we determined the number of colony-forming cells (CFC), cobblestone area forming cells (CAFC), the NOD/SCID repopulating ability (SRA), and CD34+ CD38- subset by phenotyping. The highest fold-increase obtained for the number of nucleated cells (nc), CD34+, CD34+ CD38 cell numbers and CFC content was, respectively, 102 +/- 76, 24 +/- 19, 190 +/- 202 and 53 +/- 37 for stroma-free and 315 +/- 110, 25 +/- 3, 346 +/- 410 and 53 +/- 43 for stroma-supported cultures. CAFC week type 6 was maximally 11-fold expanded both under stroma-free and stroma-supported conditions. The FBMD-1 stromal cells supported a modest expansion of CD34+ CD38- cells (27 +/- 18-fold) and nc (6 +/- 4-fold), while a loss of CFC and CAFC subsets was observed. The stromal cells synergized with FL + TPO to give the highest expansion of hemopoietic progenitors. Stromal support could be fully replaced by complementing the FL + TPO stimulated cultures with SCF + IL6. FL + TPO were required and sufficient to give a 10- to 20-fold expansion of the ability of CD34+ UCB cells in 2-week cultures to engraft the BM of NOD/SCID mice. Stromal support, or complementation of the medium with SCF + IL6, did not significantly improve the in vivo engraftment potential. If the SRA and CAFC week 6 assays are accepted as tentative estimates of in vivo engrafting stem cells in humans, our findings may assist in the preparation of UCB grafts to meet the requirements for improved repopulation in the clinical setting.
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PMID:Successful short-term ex vivo expansion of NOD/SCID repopulating ability and CAFC week 6 from umbilical cord blood. 1106 30

Current technology to numerically expand hemopoietic stem/progenitor cells (HSPC) ex vivo within 1 to 2 weeks is insufficient to warrant significant gain in reconstitution time following their transplantation. In order to more stringently test the parameters affecting HSPC expansion, we followed ex vivo cultures of CD34+-selected umbilical cord blood (UCB) HSPC for up to 10 weeks and investigated the effects of stromal support and cytokine addition. The cytokine combinations included FL + TPO, FL + TPO plus SCF and/or IL6, or SCF + IL6. To identify the HSPC in uncultured and cultured material, we determined the number of colony-forming cells (CFC), cobblestone area forming cells (CAFC), the NOD/SCID repopulating ability (SRA), and CD34+ subsets by phenotyping. The highest fold-increase obtained for CD34+ and CD34+ CD38- cell numbers was, respectively, 1197 and 30,937 for stroma-free and 4066 and 117,235 for stroma-supported cultures. In general, CFC generation increased weekly in FL + TPO containing groups up to week 5 with a 28- to 195-fold expansion whereafter the weekly CFC output stabilized. Stroma support enhanced the expansion of CAFC week 6 maximally 11-fold to 89-fold with FL + TPO + IL6. Cultures stimulated with at least FL + TPO gave an estimated 10- to 14-fold expansion of the ability of CD34+ UCB cells to multilineage engraft the BM of sublethally irradiated NOD/SCID mice at 2 weeks of stroma-free and stroma-supported cultures, while at week 5 and later the estimated SRA decreased to low or undetectable levels in all groups. Our results show that stroma and FL + TPO but also inclusion of bovine serum albumin, greatly increase the long-term generation of HSPC as measured by in vitro assays and is indispensable for long-term expansion of CD34+ CD38- CXCR4+ cells. However, the different surrogate methods to quantify the HSPC (CD34+ CD38-, CFC, CAFC week 6 and SRA) show increasing incongruency with increasing culture time, while especially the phenotypic analysis and the CFC generation greatly overestimate the CAFC and SRA expansion in 10-week cultures.
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PMID:Stromal support augments extended long-term ex vivo expansion of hemopoietic progenitor cells. 1151 95

A new thyroid cancer cell line, KTC-2, was established from the malignant pleural effusion of a patient with recurrent thyroid cancer associated with anaplastic transformation from thyroid papillary cancer. Karyotype analysis showed a mode of 109 chromosomes. Subcutaneous cell injections produced small regressing tumors in athymic or severe combined immunodeficiency disorders (SCID) mice. Histologic examination showed anaplastic tumor cells surrounded by prominent mononuclear cells. An expression of thyroglobulin, thyroid transcription factor-1, and PAX-8 but not thyroid peroxidase and thyrotropin (TSH) receptor was detected. Biochemical analysis revealed secretion of interleukin (IL)-6, parathyroid hormone-related protein (PTHrP), and granulocyte-macrophage colony-stimulating factor. All the cytokines are known to induce paraneoplastic syndromes in patients with anaplastic thyroid cancer. Our previous studies revealed that medroxyprogesterone acetate (MPA) reduces secretion of IL-6 and PTHrP from human breast cancer cells. To investigate the regulatory mechanisms of secretion of these cytokines, MPA was administered to the KTC-2 cells. MPA dose-dependently decreased the secretion and mRNA expression of IL-6 and PTHrP. Expression of androgen receptor and glucocorticoid receptor (GR) but not progesterone receptor was detected. Dexamethasone but not dihydrotestosterone and progesterone decreased IL-6 and PTHrP secretion. These findings suggest that MPA decreases IL-6 and PTHrP secretion as a glucocorticoid mediated by GR in the KTC-2 cells. This KTC-2 cell line may be a suitable model for developing new strategies against paraneoplastic syndromes caused by anaplastic thyroid cancer.
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PMID:Medroxyprogesterone acetate decreases secretion of interleukin-6 and parathyroid hormone-related protein in a new anaplastic thyroid cancer cell line, KTC-2. 1272 73

We assessed a nonradioactive approach to induce apoptosis in non-small cell lung cancer by a novel iodide uptake and retention mechanism. To enhance tumor apoptosis, we transduced non-small cell lung cancer cells with retroviral vectors containing the sodium iodide symporter (NIS) and thyroperoxidase (TPO) genes. Expression of NIS and TPO facilitated concentration of iodide in tumors. As a consequence of the marked increase in intracellular levels of iodide, apoptosis was seen in >95% of NIS/TPO-modified lung cancer cells. Intraperitoneal injection of potassium iodide resulted in significant tumor volume reduction in NIS/TPO-modified tumor xenografts without apparent adverse effects in SCID mice. Iodide induced an increase in the level of reactive oxygen species. Iodide-induced apoptosis is sensitive to N-acetylcysteine inhibition, suggesting an important role by reactive oxygen species in this apoptotic process. In addition, iodide-induced apoptosis is associated with overexpression of CDKN1A (p21/Waf1)and down-regulation of survivin at both mRNA and protein levels. This is the first report demonstrating that a therapeutic dose of nonradioactive iodide has potent efficacy and high selectivity against lung cancer when used in combination with genetic modification of cancer cells to express the NIS/TPO genes.
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PMID:Nonradioactive iodide effectively induces apoptosis in genetically modified lung cancer cells. 1294 36

To improve maintenance and gene transfer of human lymphoid progenitors for clinical use in gene therapy of adenosine deaminase (ADA)-deficient SCID we investigated several gene transfer protocols using various stem cell-enriched sources. The lymphoid differentiation potential was measured by an in vitro clonal assay for B/NK cells and in the in vivo SCID-hu mouse model. Ex vivo culture with the cytokines TPO, FLT3-ligand, and SCF (T/F/S) plus IL-3 or IL-7 substantially increased the yield of transduced bone marrow (BM) CD34(+) cells purified from ADA-SCID patients or healthy donors, compared to T/F/S alone. Moreover, the use of IL-3 or IL-7 significantly improved the maintenance of in vitro B cell progenitors from ADA-SCID BM cells and allowed the efficient transduction of B and NK cell progenitors. Under these optimized conditions transduced CD34(+) cells were efficiently engrafted into SCID-hu mice and gave rise to B and T cell progeny, demonstrating the maintenance of in vivo lymphoid reconstitution capacity. The protocol based on the T/F/S + IL-3 combination was included in a gene therapy clinical trial for ADA-SCID, resulting in long-term engraftment of stem/progenitor cells. Remarkably, gene-corrected BM CD34(+) cells obtained from one patient 4 and 11 months after gene therapy were capable of repopulating the lymphoid compartment of SCID-hu hosts.
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PMID:IL-3 or IL-7 increases ex vivo gene transfer efficiency in ADA-SCID BM CD34+ cells while maintaining in vivo lymphoid potential. 1556 41

The development of leukemias in several children with severe combined immunodeficiency disease who were transplanted with retroviral vector-transduced bone marrow cells has renewed concerns about the risks associated with the random integration of proviral sequences into chromosomal DNA. One theoretical way to reduce the risks of insertional mutagenesis would be to employ transduction/transplantation protocols that minimize the total number of genetically modified cells and associated proviral integration "events" introduced into recipients. Toward this end, we have developed a transduction protocol that involves the short-term incubation of highly purified murine stem cells with high-titer recombinant lentivirus vectors in the presence of serum-free medium and the cytokines SCF and TPO. Competitive repopulation studies showed that stem cells transduced in this way possessed the same reconstitutive ability as fresh, unmanipulated cells. Animals transplanted with only 200-2000 transduced cells were efficiently reconstituted with the genetically modified cells, and most hematopoietic cells in the recipients expressed the transgene. In contrast, the use of high-titer oncoretroviral vectors in conjunction with the same transduction/transplantation protocol resulted in only low levels of gene marking in vivo. The use of a similar transduction/transplantation strategy in future clinical studies may offer distinct advantages over current protocols.
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PMID:Efficiency of transduction of highly purified murine hematopoietic stem cells by lentiviral and oncoretroviral vectors under conditions of minimal in vitro manipulation. 1592 64


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